How Metformin Works For Cancer Prevention

haidut

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Mar 18, 2013
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The drug Metformin is currently" fashionable" to take as a cancer prevention measure. I know Peat is not a fan of it and this study probably explains why. Metformin is a mitochondrial inhibitor and mimics calorie restriction. So, I can see why mainstream medicine likes it, and why Peat is wary of it. More importantly, the study hints that drugs that inhibit glycolysis will be a good cancer prevention tool.

http://elifesciences.org/content/3/e02242

"...Recent epidemiological and laboratory-based studies suggest that the anti-diabetic drug metformin prevents cancer progression. How metformin diminishes tumor growth is not fully understood. In this study, we report that in human cancer cells, metformin inhibits mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration. Metformin inhibited cellular proliferation in the presence of glucose, but induced cell death upon glucose deprivation, indicating that cancer cells rely exclusively on glycolysis for survival in the presence of metformin. Metformin also reduced hypoxic activation of hypoxia-inducible factor 1 (HIF-1). All of these effects of metformin were reversed when the metformin-resistant Saccharomyces cerevisiae NADH dehydrogenase NDI1 was overexpressed. In vivo, the administration of metformin to mice inhibited the growth of control human cancer cells but not those expressing NDI1. Thus, we have demonstrated that metformin's inhibitory effects on cancer progression are cancer cell autonomous and depend on its ability to inhibit mitochondrial complex I."
 

LeeLemonoil

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Sep 24, 2016
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Interesting with regard to mitohormesis influence of Metformin. I'm unsure it's really so risky/negative a substance as Haidut seems to conclude, but a compelling conclusion is hard to make


Metformin reverses TRAP1 mutation-associated alterations in mitochondrial function in Parkinson’s disease | Brain | Oxford Academic

Abstract
The mitochondrial proteins TRAP1 and HTRA2 have previously been shown to be phosphorylated in the presence of the Parkinson’s disease kinase PINK1 but the downstream signalling is unknown. HTRA2 and PINK1 loss of function causes parkinsonism in humans and animals. Here, we identified TRAP1 as an interactor of HTRA2 using an unbiased mass spectrometry approach. In our human cell models, TRAP1 overexpression is protective, rescuing HTRA2 and PINK1-associated mitochondrial dysfunction and suggesting that TRAP1 acts downstream of HTRA2 and PINK1. HTRA2 regulates TRAP1 protein levels, but TRAP1 is not a direct target of HTRA2 protease activity. Following genetic screening of Parkinson’s disease patients and healthy controls, we also report the first TRAP1 mutation leading to complete loss of functional protein in a patient with late onset Parkinson’s disease. Analysis of fibroblasts derived from the patient reveal that oxygen consumption, ATP output and reactive oxygen species are increased compared to healthy individuals. This is coupled with an increased pool of free NADH, increased mitochondrial biogenesis, triggering of the mitochondrial unfolded protein response, loss of mitochondrial membrane potential and sensitivity to mitochondrial removal and apoptosis. These data highlight the role of TRAP1 in the regulation of energy metabolism and mitochondrial quality control. Interestingly, the diabetes drug metformin reverses mutation-associated alterations on energy metabolism, mitochondrial biogenesis and restores mitochondrial membrane potential. In summary, our data show that TRAP1 acts downstream of PINK1 and HTRA2 for mitochondrial fine tuning, whereas TRAP1 loss of function leads to reduced control of energy metabolism, ultimately impacting mitochondrial membrane potential. These findings offer new insight into mitochondrial pathologies in Parkinson’s disease and provide new prospects for targeted therapies.
 

Tenglish

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Nov 18, 2015
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I am also curious at the relative benefits of metformin or its supplement alternatives (berbarine/curcumin/ and maybe many other mild hormetic toxins). Clearly, if our thyroid is working optimally we will also keep lower blood sugar as more sugar is used systemically. Recently taking small amounts of either metromin or curcumin sent me into hypoglycemia (low blood pressure/mildly dizzy/low focus stamina), so I'm not a fan for practical reasons. I'm all for higher metabolism through-out life...but curiously, I do not see similar data from the masses of T4 patients similar to diabetics on glucophage with reduced mortality curves. I would like to see such...maybe its just not as readily prepared, but we would think its is equally incentivised by big pharma. I guess this really just hints on the possibility of hormesis and dose dependance when it come to most/all substances or other stressors. On a related hormetic note this Cobalt-60 study flies in the face of how we Peaters typically think of radiation: "Effects of Cobalt-60 Exposure on Health of Taiwan Residents Suggest New Approach Needed in Radiation Protection" The people exposed to such an experiment seemed to have an order of magnitude drop in various diseases. I know RP has laughed off this kind of publication as propaganda, but I would suggest we try to make a synthesis, there must be a way to account for appropriate stressors in the context of a systemic ability to deal with stress (i.e. high metabolic throughput). Perhaps some categories of stressors are never hormetic. Thoughts?
 

Spokey

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Mar 24, 2014
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316
Isn't there also some connection between lactic acid and metformin?
 
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